The behavioral, neurological, and electrophysiological effects of benzodiazepine agonists and inverse agonists are neutralized or reversed by flumazenil through its interaction with central benzodiazepine receptors. Hepatic encephalopathy can benefit from flumazenil in certain cases, however until well planned clinical trials can be carried out, hepatic encephalopathy must be treated as an exploratory indication. Although flumazenil can restore the drowsiness brought on by benzodiazepines either by alone or in conjunction with other medications, it shouldn't be taken if cyclic antidepressant toxicity is suspected [1]. In the raised plus maze and light/dark test, flumazenil (1 mg/kg) significantly reduces anxiety in BALB/c mice [2]. In rats, the decrease in allopregnanolone can be successfully stopped by flumazenil (10 mg/kg) [3]. In mice, the anticonvulsant and side effects of diazepam are countered by flumazenil (5–20 mg/kg), but not by GYKI 52466. The anticonvulsant activity of NBQX was somewhat diminished by flumazenil in the MES model, but not in the PTZ trial [4]. Reduced open-arm time and open-arm entry percentage are the outcomes of long-term ethanol treatment because flumazenil (3.0 mg/kg) inhibits withdrawal alterations [5].

Absorption, Distribution and Excretion
Flumazenil is completely (99%) metabolized. Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces.
0.9 to 1.1 L/kg
1 L/hr/kg [healthy volunteers receiving a 5-minute infusion of a total of 1 mg]

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Metabolism / Metabolites
Hepatic. Flumazenil is completely (99%) metabolized. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate.

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Biological Half-Life
Initial distribution half-life is 4 to 11 minutes and the terminal half-life is 40 to 80 minutes. Prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of flumazenil during breastfeeding. Because flumazenil is not orally absorbed it is unlikely to adversely affect the breastfed infant. If the mother requires flumazenil, it is not a reason to discontinue breastfeeding. The half-life of the drug is 54 minutes, so withholding breastfeeding for 4 to 5 hours after a dose should minimize transfer to the infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Protein binding is approximately 50%, mostly (66%) to albumin. Protein binding is reduced in patients with hepatic cirrhosis.

[1]. Flumazenil: a benzodiazepine antagonist. Clin Pharm. 1993 Sep;12(9):641-56; quiz 699-701.

[2]. Flumazenil induces benzodiazepine partial agonist-like effects in BALB/c but not C57BL/6 mice. Psychopharmacology (Berl). 2000 Jan;148(1):24-32.

[3]. Flumazenil blocks the anxiolytic action of allopregnanolone. Eur J Pharmacol. 1995 Jul 25;281(1):113-5.

[4]. Effects of the non-NMDA antagonists NBQX and the 2,3-benzodiazepine GYKI 52466 on different seizure types in mice: comparison with diazepam and interactions with flumazenil. Br J Pharmacol. 1994 Dec;113(4):1349-57.

[5]. Flumazenil blockade of anxiety following ethanol withdrawal in rats. Psychopharmacology (Berl). 1997 Jun;131(4):354-60.

Flumazenil is an organic heterotricyclic compound that is 5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine which is substituted at positions 3, 5, 6, and 8 by ethoxycarbonyl, methyl, oxo, and fluoro groups, respectively. It is used as an antidote to benzodiazepine overdose. It has a role as a GABA antagonist and an antidote to benzodiazepine poisoning. It is an ethyl ester, an organofluorine compound and an imidazobenzodiazepine.
Fumazenil is an imidazobenzodiazepine derivative and a potent benzodiazepine receptor antagonist that competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex, thereby reversing the effects of benzodiazepine on the central nervous system.
Flumazenil is a Benzodiazepine Antagonist.
Flumazenil is an imidazo-benzodiazepine derivative, effective in reversing benzodiazepine-induced activities. Flumazenil antagonizes the benzodiazepine binding site of the gamma-aminobutyric acid (GABA)/benzodiazepine receptor complex in the central nervous system (CNS), thereby preventing the chloride channel opening events and inhibiting neuronal hyperpolarization. As a result, flumazenil reverses benzodiazepine-induced effects including sedation, psychomotor deficits, amnesia, and hypoventilation in a dose-dependent manner.
A potent benzodiazepine receptor antagonist. Since it reverses the sedative and other actions of benzodiazepines, it has been suggested as an antidote to benzodiazepine overdoses.

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Drug Indication
For the complete or partial reversal of the sedative effects of benzodiazepines in cases where general anesthesia has been induced and/or maintained with benzodiazepines, and where sedation has been produced with benzodiazepines for diagnostic and therapeutic procedures. Also for the management of benzodiazepine overdose as an adjunct for appropriate supportive and symptomatic measures.
FDA Label

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Mechanism of Action
Flumazenil, an imidazobenzodiazepine derivative, is a benzodiazepine antagonist. It competitively inhibits the benzodiazepine binding site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man.

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Pharmacodynamics
Flumazenil antagonizes the CNS effects produced by benzodiazepines, but does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids.

C15H14FN3O3

303.29

303.101

78755-81-4

3373

White to off-white solid powder

1.4±0.1 g/cm3

528.0±50.0 °C at 760 mmHg

201-203°C

273.1±30.1 °C

0.0±1.4 mmHg at 25°C

1.634

0.67

0

5

3

22

461

0

OFBIFZUFASYYRE-UHFFFAOYSA-N

InChI=1S/C15H14FN3O3/c1-3-22-15(21)13-12-7-18(2)14(20)10-6-9(16)4-5-11(10)19(12)8-17-13/h4-6,8H,3,7H2,1-2H3

ethyl 8-fluoro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2 mg/mL (6.59 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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 (Please use freshly prepared in vivo formulations for optimal results.)